Cocaine and methamphetamine are leading drug threats in the U.S. today, yet no effective treatments for their abuse are available. One strategy for developing effective anti-cocaine and methamphetamine agents is to block their access to key target proteins. Of the myriad of sites through which these psychomotor stimulants can act, CT receptors have emerged as promising targets for medication development. In our earlier funded project, we demonstrated that selective a receptor antagonists attenuate many of the toxic and stimulant effects of both cocaine and methamphetamine. Of the two major a receptor subtypes, a, and a2, we have been able to confirm the involvement of a-\ receptors in many of these effects through the development of subtype selective ligands and by using sequence specific antisense oligonucleotides against receptors. However, the sequence of cr2 receptors is still unknown and there are currently no truly selective ligands that bind to a2 receptors. The existing data are nonetheless highly suggestive of a role for a2 receptors in the effects of cocaine and methamphetamine. We therefore hypothesize that a2 receptors represent viable medication development targets for psychostimulant abuse. To test this, the specific aims of the project are: 1) To develop novel a2 receptor ligands with improved selectivity, 2) To confirm the affinity and relative selectivity of the novel a2 receptor ligands, 3) To demonstrate that selective a2 receptor ligands alter the behavioral effects of cocaine, and 4) To demonstrate that selective a2 receptor ligands alter the actions of methamphetamine in vivo. It is anticipated that the results of this project will stimulate the rational development of new a2 receptor probes and ultimately contribute to improved treatments for psychostimulant abuse.